Circulating CXCR5+CXCR3+PD-1Lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

HIV-1-specific broadly-neutralizing antibodies (bnAb) typically develop in individuals with continuous high-level viral replication and increased immune activation, conditions that cannot be reproduced during prophylactic immunization. Understanding mechanisms supporting bnAb development in the absence of high-level viremia may be important for designing bnAb-inducing immunogens. Here, we show that the breadth of neutralizing antibody responses in HIV-1 controllers was associated with a relative enrichment of circulating CXCR5+ CXCR3+ PD-1Lo CD4 T cells. These CXCR3+ PD-1Lo Tfh-like cells were preferentially induced in vitro by functionally superior dendritic cells from controller neutralizers, and able to secrete IL-21 and support B cells. In addition, these CXCR3+ PD-1Lo Tfh-like cells contain higher proportions of stem cell-like memory T cells, and upon antigenic stimulation differentiated into PD-1Hi Tfh-like cells in a Notch-dependent manner. Together, these data suggest that CXCR5+ CXCR3+ PD-1Lo cells represent a dendritic cell-primed precursor cell population for PD-1Hi Tfh-like cells that may contribute to the generation of bnAbs in the absence of high–level viremia.

HIV-1特异性广谱中和抗体（broadly-neutralizing antibodies，以下简称bnAb）通常在持续高水平病毒复制且免疫激活增强的个体中产生，此类状态无法通过预防性免疫接种复现。阐明在无高水平病毒血症的情况下支持bnAb产生的机制，对于设计可诱导bnAb的免疫原具有重要意义。本研究发现，HIV-1感染控制者体内中和抗体应答的广度，与循环CXCR5+CXCR3+PD-1Lo CD4阳性T细胞的相对富集显著相关。此类CXCR3+PD-1Lo滤泡辅助T细胞样（follicular helper T cell-like，Tfh-like）细胞在体外可优先由来自中和抗体阳性HIV-1感染控制者的功能优异的树突状细胞（dendritic cell，DC）诱导产生，且能够分泌白细胞介素21（interleukin-21，IL-21）并辅助B细胞。此外，此类CXCR3+PD-1Lo Tfh样细胞中干细胞样记忆T细胞的占比更高，且在抗原刺激后可通过Notch依赖的方式分化为PD-1Hi Tfh样细胞。综上，本研究数据表明，CXCR5+CXCR3+PD-1Lo细胞是一类由树突状细胞致敏的PD-1Hi Tfh样细胞前体细胞群，其可能在无高水平病毒血症的情况下参与bnAb的产生。